Dynamics and implications of anti-drug antibodies against adalimumab using ultra-sensitive and highly drug-tolerant assays.
Front Immunol
; 15: 1429544, 2024.
Article
em En
| MEDLINE
| ID: mdl-39238635
ABSTRACT
Background:
Adalimumab induces the production of anti-drug antibodies (ADA) that may lead to reduced drug concentration and loss-of-response, posing significant clinical challenges. However, traditional immunoassays have limitations in terms of sensitivity and drug-tolerance, hindering the insights of ADA response.Methods:
Herein, we developed an integrated immunoassay platform combining the electrochemiluminescence immunoassay with immunomagnetic separation strategy. A longitudinal cohort study involving 49 patients with ankylosing spondylitis was carried out to analyze the dynamic profiles of ADA and to investigate the impact of ADA on adalimumab pharmacokinetics using a population pharmacokinetic model. Additionally, cross-sectional data from 12 patients were collected to validate the correlation between ADA levels and disease relapse.Results:
The ADA assay demonstrated high sensitivity (0.4 ng/mL) and drug-tolerance (100 µg/mL), while the neutralizing antibodies (NAB) assay showed a sensitivity of 100 ng/mL and drug-tolerance of 20 µg/mL. Analysis of the longitudinal cohort revealed that a majority of patients (44/49, 90%) developed persistent ADA within the first 24 weeks of treatment. ADA levels tended to plateau over time after an initial increase during the early immune response phase. Further, nearly all of the tested patients (26/27, 96%) were classified as NAB positive, with a strong correlation between ADA levels and neutralization capacity (R2 = 0.83, P < 0.001). Population pharmacokinetic modeling revealed a significant positive association between model-estimated individual clearance and observed ADA levels. Higher ADA levels were associated with adalimumab clearance and disease relapse in a cross-sectional cohort, suggesting a promising ADA threshold of 10 for potential clinical application. Moreover, the IgG class was the primary contributor to ADA against adalimumab and the apparent affinity exhibited an increasing trend over time, indicating a T-cell dependent mechanism for ADA elicitation by adalimumab.Conclusion:
In summary, this integrated immunoassay platform shows promise for in-depth analysis of ADA against biologics, offering fresh insights into immunogenicity and its clinical implications.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Espondilite Anquilosante
/
Adalimumab
Limite:
Adult
/
Female
/
Humans
/
Male
/
Middle aged
Idioma:
En
Revista:
Front Immunol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
Suíça